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The projection from the lateral habenula (LHb) to the rostromedial tegmental nucleus (RMTg) transmits negative reward–related information. Here the authors show that aversive stimuli increase LHb excitatory drive onto RMTg neurons, and optogenetic stimulation of this pathway is sufficient to induce active, passive and conditioned behavioral avoidance. Lateral habenula (LHb) projections to the ventral midbrain, including the rostromedial tegmental nucleus (RMTg), convey negative reward–related information, but the behavioral ramifications of selective activation of this pathway remain unexplored. We found that exposure to aversive stimuli in mice increased LHb excitatory drive onto RMTg neurons. Furthermore, optogenetic activation of this pathway promoted active, passive and conditioned behavioral avoidance. Thus, activity of LHb efferents to the midbrain is aversive but can also serve to negatively reinforce behavioral responding.

The growing prevalence of overeating disorders is a key contributor to the worldwide obesity epidemic. Dysfunction of particular neural circuits may trigger deviations from adaptive feeding behaviors. The lateral hypothalamus (LH) is a crucial neural substrate for motivated behavior, including feeding, but the precise functional neurocircuitry that controls LH neuronal activity to engage feeding has not been defined. We observed that inhibitory synaptic inputs from the extended amygdala preferentially innervate and suppress the activity of LH glutamatergic neurons to control food intake. These findings help explain how dysregulated activity at a number of unique nodes can result in a cascading failure within a defined brain network to produce maladaptive feeding.

The prefrontal cortex is a critical neuroanatomical hub for controlling motivated behaviours across mammalian species 1 , 2 , 3 . In addition to intra-cortical connectivity, prefrontal projection neurons innervate subcortical structures that contribute to reward-seeking behaviours, such as the ventral striatum and midline thalamus 4 . While connectivity among these structures contributes to appetitive behaviours 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , how projection-specific prefrontal neurons encode reward-relevant information to guide reward seeking is unknown. Here we use in vivo two-photon calcium imaging to monitor the activity of dorsomedial prefrontal neurons in mice during an appetitive Pavlovian conditioning task. At the population level, these neurons display diverse activity patterns during the presentation of reward-predictive cues. However, recordings from prefrontal neurons with resolved projection targets reveal that individual corticostriatal neurons show response tuning to reward-predictive cues, such that excitatory cue responses are amplified across learning. By contrast, corticothalamic neurons gradually develop new, primarily inhibitory responses to reward-predictive cues across learning. Furthermore, bidirectional optogenetic manipulation of these neurons reveals that stimulation of corticostriatal neurons promotes conditioned reward-seeking behaviour after learning, while activity in corticothalamic neurons suppresses both the acquisition and expression of conditioned reward seeking. These data show how prefrontal circuitry can dynamically control reward-seeking behaviour through the opposing activities of projection-specific cell populations. Neurons that project from the prefrontal cortex to either the nucleus accumbens or paraventricular thalamus receive different inputs, differentially encode reward-predictive cues, and have opposing effects on reward seeking during cue presentation. Control of reward-seeking behaviour Projections from the prefrontal cortex to the nucleus accumbens and paraventricular thalamus contribute to reward-seeking behaviours, but the type of reward-relevant information that these prefrontal-cortex neurons encode is unknown. Garret Stuber and colleagues show that these two populations of projection neuron receive different inputs, differentially encode reward-predictive cues, and have opposing effects on reward seeking when cues are presented. These findings show how the prefrontal cortex can dynamically control reward-seeking behaviour through the opposing activities of anatomically segregated, projection-specific cell populations.

In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data.

Increased tonic activity of locus coeruleus noradrenergic (LC-NE) neurons induces anxiety-like and aversive behavior. While some information is known about the afferent circuitry that endogenously drives this neural activity and behavior, the downstream receptors and anatomical projections that mediate these acute risk aversive behavioral states via the LC-NE system remain unresolved. Here we use a combination of retrograde tracing, fast-scan cyclic voltammetry, electrophysiology, and in vivo optogenetics with localized pharmacology to identify neural substrates downstream of increased tonic LC-NE activity in mice. We demonstrate that photostimulation of LC-NE fibers in the BLA evokes norepinephrine release in the basolateral amygdala (BLA), alters BLA neuronal activity, conditions aversion, and increases anxiety-like behavior. Additionally, we report that β-adrenergic receptors mediate the anxiety-like phenotype of increased NE release in the BLA. These studies begin to illustrate how the complex efferent system of the LC-NE system selectively mediates behavior through distinct receptor and projection-selective mechanisms.

The parabrachial nucleus (PBN) is a major hub that receives sensory information from both internal and external environments. Specific populations of PBN neurons are involved in behaviors including food and water intake, nociceptive responses, breathing regulation, as well as learning and responding appropriately to threatening stimuli. However, it is unclear how many PBN neuron populations exist and how different behaviors may be encoded by unique signaling molecules or receptors. Here we provide a repository of data on the molecular identity, spatial location, and projection patterns of dozens of PBN neuron subclusters. Using single-cell RNA sequencing, we identified 21 subclusters of neurons in the PBN and neighboring regions. Multiplexed in situ hybridization showed many of these subclusters are enriched within specific PBN subregions with scattered cells in several other regions. We also provide detailed visualization of the axonal projections from 21 Cre-driver lines of mice. These results are all publicly available for download and provide a foundation for further interrogation of PBN functions and connections.

Social behaviors require neural circuits to process social cues and orchestrate motivational states. This study identifies a subpopulation of hypothalamic neurons expressing neurotensin that are engaged by social and hormonal signals. These neurons project to midbrain dopaminergic reward systems to promote and reinforce social and motivated behavior in a hormone-sensitive manner. Neural networks that control reproduction must integrate social and hormonal signals, tune motivation, and coordinate social interactions. However, the neural circuit mechanisms for these processes remain unresolved. The medial preoptic area (mPOA), an essential node for social behaviors, comprises molecularly diverse neurons with widespread projections. Here we identify a steroid-responsive subset of neurotensin ( Nts )-expressing mPOA neurons that interface with the ventral tegmental area (VTA) to form a socially engaged reward circuit. Using in vivo two-photon imaging in female mice, we show that mPOA Nts neurons preferentially encode attractive male cues compared to nonsocial appetitive stimuli. Ovarian hormone signals regulate both the physiological and cue-encoding properties of these cells. Furthermore, optogenetic stimulation of mPOA Nts –VTA circuitry promotes rewarding phenotypes, social approach and striatal dopamine release. Collectively, these data demonstrate that steroid-sensitive mPOA neurons encode ethologically relevant stimuli and co-opt midbrain reward circuits to promote prosocial behaviors critical for species survival.

Brain function during reward seeking Interactions between the basolateral amygdala (BLA) and nucleus accumbens (NAc) are involved in a number of reward-processing and addictive behaviours, but our understanding of the precise role of each of these brain areas has been limited by the inability to manipulate pathways selectively during behaviour. Stuber et al . use optogenetic technologies, in which light selectively activates or inhibits genetically-defined neuronal subpopulations, to reveal an unexpected role for the BLA — a brain region usually associated with aversive behaviours. The BLA is shown to be important for processing both positive and negative effects, but glutamatergic pathways between the BLA and NAc are specifically associated with reward-seeking behaviours. The basolateral amygdala (BLA) has a crucial role in emotional learning irrespective of valence 1 , 2 , 3 , 4 , 5 , 21 , 22 , 23 . The BLA projection to the nucleus accumbens (NAc) is thought to modulate cue-triggered motivated behaviours 4 , 6 , 7 , 24 , 25 , but our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural-circuit elements of this pathway selectively during behaviour. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibres from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. Here we show that optical stimulation of the pathway from the BLA to the NAc in mice reinforces behavioural responding to earn additional optical stimulation of these synaptic inputs. Optical stimulation of these glutamatergic fibres required intra-NAc dopamine D1-type receptor signalling, but not D2-type receptor signalling. Brief optical inhibition of fibres from the BLA to the NAc reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behaviour. Moreover, although optical stimulation of glutamatergic fibres from the medial prefrontal cortex to the NAc also elicited reliable excitatory synaptic responses, optical self-stimulation behaviour was not observed by activation of this pathway. These data indicate that whereas the BLA is important for processing both positive and negative affect, the glutamatergic pathway from the BLA to the NAc, in conjunction with dopamine signalling in the NAc, promotes motivated behavioural responding. Thus, optogenetic manipulation of anatomically distinct synaptic inputs to the NAc reveals functionally distinct properties of these inputs in controlling reward-seeking behaviours.

Natural rewards and drugs of abuse can alter dopamine signaling, and ventral tegmental area (VTA) dopaminergic neurons are known to fire action potentials tonically or phasically under different behavioral conditions. However, without technology to control specific neurons with appropriate temporal precision in freely behaving mammals, the causal role of these action potential patterns in driving behavioral changes has been unclear. We used optogenetic tools to selectively stimulate VTA dopaminergic neuron action potential firing in freely behaving mammals. We found that phasic activation of these neurons was sufficient to drive behavioral conditioning and elicited dopamine transients with magnitudes not achieved by longer, lower-frequency spiking. These results demonstrate that phasic dopaminergic activity is sufficient to mediate mammalian behavioral conditioning.

The current obesity epidemic is a major worldwide health concern. Despite the consensus that the brain regulates energy homeostasis, the neural adaptations governing obesity are unknown. Using a combination of high-throughput single-cell RNA sequencing and longitudinal in vivo two-photon calcium imaging, we surveyed functional alterations of the lateral hypothalamic area (LHA)–a highly conserved brain region that orchestrates feeding–in a mouse model of obesity. The transcriptional profile of LHA glutamatergic neurons was affected by obesity, exhibiting changes indicative of altered neuronal activity. Encoding properties of individual LHA glutamatergic neurons were then tracked throughout obesity, revealing greatly attenuated reward responses. These data demonstrate how diet disrupts the function of an endogenous feeding suppression system to promote overeating and obesity.